The Center for Narcolepsy is a multidisciplinary research program on the etiology, diagnosis, and treatment of this illness. We have brought together the critical mass of specialists in the necessary fields to advance knowledge in the area and have made very significant progress during the last funding period. A multidisciplinary approach is required because of the prime involvement of several very diverse biological systems in its pathophysiology. First, narcolepsy involves the immune system. The disorder has a very strong HLA association but does not seem to be an autoimmune disease. In the last funding period, we have identified the HLA alleles most likely to be involved and have discovered a new immune related gene that is tightly linked with the pathology in canine narcolepsy. We are therefore now at the point where we will be able to study the mechanisms of action of these genetic factors. Second, narcolepsy is a centrally mediated disorder of REM sleep that is only poorly controlled by available medications. We now have clear indications that the neurochemical defects involve hypersensitive cholinergic systems in the brainstem and the basal forebrain. it will be the over-all goal of the next funding period to understand how these immunogenetic factors interact with key neurotranmitters systems in the brain to produce narcolepsy. The proposed work is divided into four different but very inter-related scientific projects: Human Banking and Diagnosis; Linkage and Molecular Studies in Canines; Evidence for Neuronal Degeneration in Narcolepsy, and Neurochemical Studies of Narcolepsy. These projects involve research using both human material and the only available animal model, canine narcolepsy. This model provides a unique opportunity to study the fundamental neurochemical mechanisms involved in these diseases, and to rapidly test new strategies for treatment that emerge as a result of these investigations. The growing realization of the enormous personal and societal consequences resulting directly or indirectly from sleep pathologies such as narcolepsy mandate a continued investment into research in these diseases.